Biologic drugs are those drugs that are manufactured inside living organisms as opposed to chemical drugs which are produced through various chemical reactions. Biologics come in various forms like hormones, vaccines, monoclonal antibodies, blood components, genes and various proteins. These can be made up of microorganisms like how vaccines are made up of weakened forms of viruses or it could be human DNA or tissue like stem cells. Biologic drugs are difficult to manufacture and used to treat complex conditions where chemical drugs are not as effective. One of the most well known biologics is insulin – a hormone used to manage blood glucose levels.
How are biologics different from chemical drugs ?
The biggest difference between a chemical and biologic drug is size. Biologic drugs are many many times larger than chemical molecules and their structure is a lot more complex. This is why biologics are called large molecules and chemical drugs are called small molecules.
Biologics come in various sizes as do chemical drugs. Some biologic molecules, like insulin or human growth hormone are smaller in size compared to larger biologic molecules like monoclonal antibodies. But in general, the smallest biologic molecule is a lot bigger in size than the largest chemical molecule. And biologic molecules are also way more complex. It’s not just the size of the antibody, but the complexity of the bonds between the atoms that makes it much more complex than small molecule drugs.
Chemical drugs are usually oral solids like tablets and capsules whereas biologics come in the form of injectables and infusions. Biologic drugs are directly injected into the blood as taking it through the oral route would destroy the living organism. Chemical drugs are also more stable than biologic drugs and are easier to handle as they are not very sensitive to handling and storage conditions whereas biologic drugs are very sensitive and need to be handled carefully and transported in refrigerated conditions.
Uses of biologics
Biologics are mostly used to treat complex diseases for which cures are not available. They are usually prescribed to patients who are failing standard medication. Biologics are used to treat many diseases like different forms of cancer, asthma, psoriasis, ulcerative colitis and rheumatoid arthritis. All vaccines that are taken by humans, including the ones we take as children for polio and various other immunizations are biologics. They contain some biologic material or weakened forms of the viruses in them.
Most recently, the Covid vaccines received by most of us were a form of biologic drug. The Pfizer and Moderna vaccine were made using the mRNA technology which uses a molecule called messenger RNA rather than the actual bacteria or virus. The J&J vaccine, Covishield and Covaxin all use weakened forms of viruses.
Earliest Use Of Biologics
One of the earliest biologics used on humans is insulin which was manufactured by the company Eli Lilly & Co. They used to extract insulin from the pancreas of cows and pigs that they got from slaughterhouses. Animal insulin is not the same as human insulin and a lot of times caused adverse reactions in humans. But it was the only source of insulin available at the time and really helped manage diabetes to a great degree. By the 1980s, there were concerns that there weren’t enough cattle and pigs in the world to produce enough insulin for the increasing number of diabetics.
But then there was a significant leap in biotechnology. Scientists figured out a way to produce human insulin inside a bacteria called E.Coli. This type of process is called recombinant DNA technology. The gene responsible for producing insulin is inserted into the bacteria which makes the bacteria produce insulin. It is then extracted and purified to get human insulin. This process is a lot cheaper and a lot easier than producing insulin from animals and has brought down the cost of insulin significantly. The insulin produced by this method is also the exact same as the insulin produced by the human body.
Manufacturing Complexity
Biologic drugs are a lot more complex and expensive to manufacture than regular chemical drugs. Let us take a look at one of the ways to manufacture biologic drugs called recombinant DNA technology.
Various advances in biotechnology have made it possible for us to edit, add or delete genes. The manufacturing process of biologics starts with inserting the gene responsible for producing the drug into the DNA of the microorganism like E. Coli which is the bacteria used to produce insulin. The produced drug is called the biological entity in this scenario. The bacteria is then left to divide and reproduce in a cell culture. Then from this cell culture, the bacteria that produce the biological entity most efficiently are selected and added to a fermenter where they multiply in number. Now we have clones of the original bacteria that can produce the drug. We will take these clones and freeze them. This is called the Cell Bank and will be used to make this particular drug in the future. The cell bank is a safety net for the company and will be used to start a new cell line in case anything goes wrong during production.
To produce the drug, one of the vials from the cell bank is unfrozen and expanded in a bioreactor. The clones of the original bacteria will produce the drug since they have the gene to produce it. The drug will then be extracted from the bacteria and purified into the form in which it has to be delivered into the body. From there, we will make the final formulation of the drug in the form of an injectable, package it and distribute it.
This process is not only very long, but also very complex and expensive compared to chemical drugs. The complexity of manufacturing biologics lies in the conditions under which the drugs are manufactured. While chemical drugs are produced through various chemical reactions, they are not very sensitive to the environment in which they are manufactured. Biologic drugs are very sensitive to the conditions in the bioreactor. They have to be produced at a very certain temperature and at a certain level of humidity. They produce different results even if the concentration of nutrients in the cell culture are slightly different. They may not produce the intended result if there is a small change in any of these conditions. So they have to be produced in an environment that can be controlled. So if we take 2 vials from the cell bank and start a cell line in Europe and another one in the US, there will be very small differences in them unless everything is exactly replicated in the two manufacturing facilities.
Biosimilars
A biosimilar is a copy of an innovative biologic drug which can be manufactured and sold by other companies after the innovator’s patent has expired. It is important to note that biosimilars are not identical copies of the original drug, unlike chemical drugs where the chemical composition of a drug can be observed and generic companies can make exact copies of the drug. Due to the manufacturing complexity mentioned above, it is very difficult for other companies to know the exact conditions in which the innovator produced the drug. So there will always be meaningful differences in the structure of a biosimilar and the original drug. But as long as they behave the same way, and cause the same effects in the body, they are treated as equivalents of the original drug. Biosimilars are potential therapeutic alternatives, not exact copies.
The penetration of biosimilars is relatively low as there are only 31 biosimilars approved for use in the US. Of these, only 20 are being marketed. This is because a lot of biologics are relatively recent and the patents on them have not expired. But a lot of biologics are going to go off patent in the coming few years which gives an opportunity for Indian pharma companies.
Are biosimilars the same as generics?
No. Biosimilars are not generics. There are some meaningful differences between biosimilars and generics. The first one is that biosimilars are similar, not identical to the original drug whereas generics are exact copies of the original drug. As mentioned before, it is almost impossible to make an exact copy of a biologic unless you have access to the innovator’s cell bank and can replicate the exact conditions for manufacturing. Biosimilars provide the same effect in the body as the reference biologic. But they are not the exact same drug.
The second difference is that generics can be used interchangeably with the brand name drug, because they are identical copies of the drug. But a biosimilar cannot be used interchangeably with a reference biologic because the drug is not an exact copy. Some people might be allergic to the biological entity in the biosimilar or their body might not respond the same way to the biosimilar. So biosimilars cannot be used interchangeably with the reference biologic unless they prove a very high degree of similarity. This is also one of the reasons for the low penetration of biosimilars.
The third difference is that biosimilar manufacturers have to do a small clinical study before they receive approval whereas generics do not. Since it is not an exact copy, the trial is conducted to prove that the biosimilar has the exact same effect on the body as the reference biologic.
And lastly, there is significant price erosion for the drug when generics are introduced. But due the low penetration and the fact that biosimilars are not interchangeable with the reference biologic, there isn’t much erosion in the price of the original drug. Moreover, due to the manufacturing complexity and high costs, the price of biosimilars are not that much lower than that of the reference biologic.
So a good way to look at a biosimilar is that it is a drug that is a little different from the innovator drug. It is not the same drug but acts the same way in the body and treats the same disease
Approval Process
We have already discussed the drug development process in another article. The process to develop a biologic drug is the exact same as the process to manufacture a chemical drug. We go through the same steps of discovery, preclinical trials, clinical trials and then approval. At the end of the process, chemical drugs apply for an NDA – New Drug Application. In the case of biologics, companies apply for a BLA – Biologics License Application.
A biosimilar’s development timeline is different from that of generics. The US FDA has an abbreviated pathway for the approval of biosimilars as well, but the time it takes is much longer than generics. Since they don’t have to go through discovery, their process starts from development of the molecule where they reverse engineer the innovator drug. They have to do some preclinical studies and a few studies in humans as well. At the end of it all they submit an ABLA – Abbreviated Biologics License application. It takes 8 to 10 years and costs about $100-200 million. In comparison, generics get approval in 4 years and cost about $1-2 million to develop.
A Biologics License Application requires most of the same data that is needed for an NDA. They have to submit data from animal studies, human trials and information about the drugs characteristics and manufacturing. An ABLA requires studies that demonstrate that the biosimilar product works the exact same way in the body as the reference biologic even though the molecule is not the exact same. Apart from that, they too have to submit data regarding the animal and human trials and manufacturing information.
Importance of biosimilars
Biologic drugs are low volume high value products. In 2020, 5 of the top 10 drugs sold in the US were biologics. In fact, the top selling drug in 2020 was Humira, which is a biologic. Overall, biologics are the most expensive drugs available on the market and are desperately needed by patients who suffer from certain conditions.
As the competition in biosimilars increases, the price for these drugs should come down. Lower cost medication is extremely important for people with life threatening conditions. In 2020, biosimilars helped save patients about $7.9 Billion. That number will only go up as more players enter the space and bring down the prices.
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